Article

Selective Anesthesia-induced Neuroinflammation in Developing Mouse Brain and Cognitive Impairment

Attending Anesthesiologist, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University, Shanghai, People's Republic of China. † Senior Research Technologist, ‡ Research Fellow, ‡‡ Associate Professor, Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts. § Research Fellow, Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine
Anesthesiology (Impact Factor: 5.88). 01/2013; 118(3). DOI: 10.1097/ALN.0b013e3182834d77
Source: PubMed

ABSTRACT

Background:
: Recent population studies have suggested that children with multiple exposures to anesthesia and surgery at an early age are at an increased risk of cognitive impairment. The authors therefore have established an animal model with single versus multiple exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different types of anesthesia in cognitive impairment.

Methods:
: Six- and 60-day-old mice were exposed to various anesthesia regimens. The authors then determined the effects of the anesthesia on learning and memory function, levels of proinflammatory cytokine interleukin-6 and tumor necrosis factor-α in brain tissues, and the amount of ionized calcium-binding adaptor molecule 1-positive cells, the marker of microglia activation, in the hippocampus.

Results:
: In this article, the authors show that anesthesia with 3% sevoflurane for 2 h daily for 3 days induced cognitive impairment and neuroinflammation (e.g., increased interleukin-6 levels, 151 ± 2.3% [mean ± SD] vs. 100 ± 9.0%, P = 0.035, n = 6) in young but not in adult mice. Anesthesia with 3% sevoflurane for 2 h daily for 1 day and 9% desflurane for 2 h daily for 3 days induced neither cognitive impairment nor neuroinflammation. Finally, an enriched environment and antiinflammatory treatment (ketorolac) ameliorated the sevoflurane-induced cognitive impairment.

Conclusions:
: Anesthesia-induced cognitive impairment may depend on developmental stage, anesthetic agent, and number of exposures. These findings also suggest the cellular basis and the potential prevention and treatment strategies for anesthesia-induced cognitive impairment, which may ultimately lead to safer anesthesia care and better postoperative outcomes for children.

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Available from: Yiying Zhang, Jun 12, 2015
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    • "Firstly, NIRS oximeters were put on forehead and reflected the condition of superficial cerebral cortex, so it might miss embolism, hypoperfusion and desaturation far from superficial cortex [46] . Secondly, Neurotoxicity such as neuroinflammation and Aβ generation also contribute to POCD474849, which affect the predictive performance of ScO 2 . Thirdly, even if absolute value of 50 and 80 % of baseline were regarded as safe limits for ScO 2 to prevent cerebral ischemia, cognitive dysfunction were still observed in the present and previous studies [13]. "
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    ABSTRACT: Background Postoperative cognitive dysfunction (POCD) is a frequent complication in elderly patients undergoing major non-cardiac surgery, but its etiology is still unclear. Cerebral oxygen saturation (ScO2) represents the balance of cerebral oxygen supply and demand. The aim of present study was to evaluate the relationship between perioperative ScO2 and POCD, and to verify the hypothesis that the value of ScO2 after multiple perioperative influential factors could predict POCD in elderly patients undergoing total knee arthroplasty (TKA). Methods Seventy eight Patients aged more than 65 years undergoing elective TKA with intrathecal anesthesia were enrolled. Cognitive functions were assessed one day before and 6 days after surgery, and POCD were defined according to ISPOCD. Demographics were recorded. Perioperative ScO2, blood pressure (BP), blood gas analysis and other clinical data were monitored and recorded, then the decrease of ScO2, BP and PaO2 after influential factors were calculated. Results POCD occurred in 15 patients (19.2 %). BP decreased after anesthesia induction and tourniquet deflation, and PaO2 decreased after cement implantation was higher in POCD group. ScO2 of POCD group is significantly lower than non-POCD group (P < 0.05), and the absolute value and percentage decrease of ScO2 became significant between two groups after multiple influential factors. ScO2 after all influential factors (anesthesia induction, cement implantation and tourniquet deflation) had the best predictive performance for POCD (AUC = 0.742), and the optimal threshold was 66.5 %. Conclusions Perioperative ScO2 of patients with POCD is lower than patients without POCD. ScO2 after multiple perioperative influential factors could be an effective predictor for POCD, which reveal an important role of ScO2 decrease in the development of POCD and provide possible treatment target.
    Full-text · Article · Dec 2015 · BMC Anesthesiology
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    • "Intranasal insulin administration prior to anesthesia is capable of preventing AD-like tau hyperphosphorylation in 3xTg-AD mice, a commonly used transgenic model of AD [11]. Tau hyperphosphorylation , a pathological hallmark of AD, is increased with anesthetic exposure [12] and can cause significant learning and memory deficits in aged rodents [13] [14]. As enhanced brain insulin signaling improves memory processes in cognitively healthy humans and possesses neuroprotective properties, it was hypothesized that increasing brain insulin concentrations in AD patients would prevent or slow the development of this devastating disease. "
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    ABSTRACT: Intranasal insulin has shown efficacy in patients with Alzheimer's disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory deficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain.
    Full-text · Article · Aug 2015 · Journal of Alzheimer's disease: JAD
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    • "In fact, there is evidence that volatile anesthetics can alter synaptogenesis and dendritic spine density even in the absence of cell death [43]. In addition, anesthetics have been shown to result in significant neuroinflammation [41], changes in cell signaling [44], and stem cell proliferation [45], [46]. It is likely that anesthetic effects on these processes of brain development contribute to the ultimate cognitive outcome. "
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    ABSTRACT: Background Anesthetic exposure early in life affects neural development and long-term cognitive function, but our understanding of the types of memory that are altered is incomplete. Specific cognitive tests in rodents that isolate different memory processes provide a useful approach for gaining insight into this issue. Methods Postnatal day 7 (P7) rats were exposed to either desflurane or isoflurane at 1 Minimum Alveolar Concentration for 4 h. Acute neuronal death was assessed 12 h later in the thalamus, CA1-3 regions of hippocampus, and dentate gyrus. In separate behavioral experiments, beginning at P48, subjects were evaluated in a series of object recognition tests relying on associative learning, as well as social recognition. Results Exposure to either anesthetic led to a significant increase in neuroapoptosis in each brain region. The extent of neuronal death did not differ between groups. Subjects were unaffected in simple tasks of novel object and object-location recognition. However, anesthetized animals from both groups were impaired in allocentric object-location memory and a more complex task requiring subjects to associate an object with its location and contextual setting. Isoflurane exposure led to additional impairment in object-context association and social memory. Conclusion Isoflurane and desflurane exposure during development result in deficits in tasks relying on associative learning and recognition memory. Isoflurane may potentially cause worse impairment than desflurane.
    Full-text · Article · Aug 2014 · PLoS ONE
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Questions & Answers about this publication

  • Bobbi Fleiss added an answer in Histology:
    Which chemical injectable anesthesia does not have any negative effects on neuron cells? Or has little side effects on these cells...
    I want do histochemical tests on CNS cells, but animal (mouse) must be under anesthesia. I have forced to do injectable anesthesia, but for example ketamine has a neurotoxic effect and causes apoptosis. Which injectable anesthesia protocol is suitable for mouse CNS study?

    I work on gene delivery to CNS, on prenatal and postnatal mouse. so I need both the embryo and adult spinal cord and brain to do immunohistological tests.
    Bobbi Fleiss
    It is difficult to say precisely as mouse strains differ. 40 min is a long surgery for a pregnant mouse, but the only good data on the effects on neurotoxicity use exposure times of 3+ hours or repetitive exposures. Perhaps you need to consider the effect size in your concerns about this - 6 hours of Isofulrane in the immature monkey increases cell death but its still low and in a model of hypoxia/ischemia no one probably would have noticed. If you are very concerned, compare a group of non-anesthesia with just straight culled. I think you have to bite the bullet and use what you have (which is very typical). The only suggestion I would make is that inhalational anaesthetics can be quickly removed and titrated to breathing rate so that is what I prefer. Also, see paper by Steven Back, published in Annals of Neurology using monkeys.
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      [Show abstract] [Hide abstract]
      ABSTRACT: Background: : Recent population studies have suggested that children with multiple exposures to anesthesia and surgery at an early age are at an increased risk of cognitive impairment. The authors therefore have established an animal model with single versus multiple exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different types of anesthesia in cognitive impairment. Methods: : Six- and 60-day-old mice were exposed to various anesthesia regimens. The authors then determined the effects of the anesthesia on learning and memory function, levels of proinflammatory cytokine interleukin-6 and tumor necrosis factor-α in brain tissues, and the amount of ionized calcium-binding adaptor molecule 1-positive cells, the marker of microglia activation, in the hippocampus. Results: : In this article, the authors show that anesthesia with 3% sevoflurane for 2 h daily for 3 days induced cognitive impairment and neuroinflammation (e.g., increased interleukin-6 levels, 151 ± 2.3% [mean ± SD] vs. 100 ± 9.0%, P = 0.035, n = 6) in young but not in adult mice. Anesthesia with 3% sevoflurane for 2 h daily for 1 day and 9% desflurane for 2 h daily for 3 days induced neither cognitive impairment nor neuroinflammation. Finally, an enriched environment and antiinflammatory treatment (ketorolac) ameliorated the sevoflurane-induced cognitive impairment. Conclusions: : Anesthesia-induced cognitive impairment may depend on developmental stage, anesthetic agent, and number of exposures. These findings also suggest the cellular basis and the potential prevention and treatment strategies for anesthesia-induced cognitive impairment, which may ultimately lead to safer anesthesia care and better postoperative outcomes for children.
      Full-text · Article · Jan 2013 · Anesthesiology